Some of the compounds of Formula I have previously been suggested, e.g. in U.S. Pat. No. 4,443,448, as having among others neuroleptic activity, but such activity was very weak and practically non-existent, meaning that the compounds were found completely without value in the treatment of psychoses and depressions.
It has now surprisingly been found that the compounds of Formula I, of which several are novel compounds, have a high antiserotonergic activity which, together with no neuroleptic activity, make them useful as potential antihypertensive agents. Moreover, such antiserotonergic activity make them of potential interest in the treatment of other cardiovascular diseases such as peripheral vascular diseases, trombolic or embolic episodes, cardiopulmonary emergencies etc. Furthermore, such selective 5HT.sub.2 -antagonists are potential antianxiety agents.
Only trans-isomers of the claimed compounds are active, cis-isomers being without significant 5-HT.sub.2 antagonistic activity. Furthermore, it has been found for the resolved compounds that the 5-HT.sub.2 antagonistic activity predominantly resides in the 1R,3S-enantiomers.
Preferred examples of Formula I are compounds wherein R.sub.1 is hydrogen or fluorine, n=2, X=O or S, Z=--(CH.sub.2).sub.2 -- and Y=N--R.sub.2 ; R.sub.2 =H, lower alkyl(1-3 carbon atoms), as having particularly strong antiserotonergic activity without undesired side effects.
This invention also includes pharmaceutically acceptable salts of the compounds of Formula I formed with non-toxic organic acids. Such salts are easily prepared by methods known to the art. The base is reacted with either the calculated amount of organic or inorganic acid in an aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromo-theophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts, which is wellknown to the art.
The compounds of Formula I as well as the pharmaceutically acceptable acid addition salts thereof may be administered both orally and parenterally, for example in the form of tablets, capsules, powders, syrups or solutions for injection.
The invention moreover relates to a method for the preparation of the novel indanes of Formula I, which comprises
(a) reacting a compound of the following formula II ##STR2## with a compound of formula ##STR3## wherein R.sub.1, n, X, Y and Z are as defined above, and A is halogen is OSO.sub.2 R, wherein R is alkyl (e.g. CH.sub.3) or aryl (e.g. --C.sub.6 H.sub.4 --CH.sub.3)
(b) reacting a compound of formula III ##STR4## wherein R.sub.1, R.sub.2, and n are as defined above with urea or with CS.sub.2 to give a compound of Formula I, wherein X is O or S respectively, or
(c) reacting a compound of formula IV ##STR5## with a compound of formula ##STR6## wherein R.sub.1, n, X, Y and Z are as defined above, and A is halogen or OSO.sub.2 R, wherein R is alkyl (e.g. CH.sub.3) or aryl (e.g.) --C.sub.6 H.sub.4 --CH.sub.3), or
(d) reacting a compound of Formula I, wherein X=O with P.sub.2 S.sub.5 or Lawessons reagent to produce the corresponding compound wherein X is S, whereupon the compound of Formula I is isolated as the free amine or an acid addition salt thereof and, if desired, separated in the individual isomers by conventional means.
The preparation of compounds of formula II and formula IV has been described in U.S. Pat. No. 4,443,448 and in J. Med. Chem. 26, 935 (1983).
Method (a) is preferbly carried out in an inert solvent such as methyl ethylketone or methyl isobutylketone in the presence of an alkali metal carbonate such as potassium carbonate, or another alkaline substance at reflux temperatures.
The compounds of formula ##STR7## belonging to the chemical classes of 2-imidazolidinones, and -thiones, 2-oxazolidinones and -thiones, 2-pyrrolidinones and -thiones, 2-pyrimidinones and -thiones, benzimidazolidinones and -thiones and 2,4-quinazolidinones and -thiones were prepared according to methods established in the literature.
Method (b) is preferably carried out by treating a compound of Formula III in an inert solvent such as butanol or pentanol with urea or carbondisulfide succeeded by heating at reflux temperatures.
Method (c) is preferably carried out in an inert solvent such as methyl ethylketone or ethanol in the presence of an alkali metal carbonate such as potassium carbonate, or another alkaline substance at reflux temperatures.
Method (d) is preferably carried out in hexamethyl phosphorous triamide (H MPA) or xylene at temperatures between 110.degree. C. and about 200.degree. C.
Optical resolutions of racemic trans-isomers is preferably carried out by fractional crystallization of diastereomeric salts of compound I and optically active acids such as tartaric acid, dibenzoyltartaric acid, mandelic acid etc.
Especially interesting compounds are the following:
(+)Trans-1-[3-(4-fluorophenyl)-indan-1-yl]-4-[2-(2-imidazolidinon-1-yl)ethy l]piperazine. PA0 Trans-1-[3-(4-fluorophenyl)-indan-1-yl]-4-[2-(imidazolidin-2-thion-1-yl)eth yl]piperazine. PA0 (+)Trans-1-[3-(4-fluorophenyl)-6-fluoroindan-1-yl]-4-[2-(2-imidazolidinon-1 -yl)ethyl]piperazine. PA0 (+)Trans-1-[3-(4-fluorophenyl)-6-fluoroindan-1-yl]-4-[2-(3-methyl-2-imidazo lidinon-1-yl)ethyl]piperazine. PA0 Trans-1-[3-(4-fluorophenyl)-6-chloroindan-1-yl]-4-[2-(2-imidazolidinon-1-yl )ethyl]piperazine, L(+)tartrate. PA0 Trans-1-[3-(4-fluorophenyl)-6-methylindan-1-yl]-4-[2-(2-imidazolidinon-1-yl )ethyl]piperazine. PA0 Trans-1-[3-(4-fluorophenyl)-6-methylthioindan-1-yl]-4-[2-(2-oxazolidinon-3- yl)ethyl]piperazine.
The methods of the invention shall be illustrated in the following by some examples, which may not be construed as limiting: